[unreadable] [unreadable] Substantial biologic evidence indicates that the pigmentation pathway plays a critical role in protecting against skin cancer. However, the importance of common inherited variants in the pigmentation pathway and their interactions with constitutional host factors and UV exposure history in causing skin cancer is largely unknown. Sparse data exist except for the melanocortin 1 receptor (MC1R) genetic variants. We propose to examine in detail the genetic variants in the pigmentation pathway with the risks of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) simultaneously in a nested case- control study within the Nurses Health Study (219 melanoma cases, 286 SCC cases, 300 BCC cases, and 874 matched controls). This innovative work will move this field forward, by evaluating common variants in the pigmentation pathway using complementary approaches, i.e. to evaluate putative functional SNPs and to choose tag- SNPs to test for associations of unknown common functional variants with skin cancer risk, along with exploratory pathway analyses. In addition, we will also assess the interactions between genetic variants in these genes and constitutional host factors and UV exposure history on skin cancer risk. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohort, including cohort characteristics, quality of design, high follow-up rate, large sample size, rigor in prospective host risk factor assessment, and high response rate of retrospective questionnaires. Our study will also take advantage of the previously confirmed cases of the three types of skin cancers, stored blood and DNA samples, as well as previously collected information on host risk factors and UV exposure history. This research will contribute to the scientific basis for identifying high-risk individuals for skin cancer and providing individualized risk management strategies. [unreadable] [unreadable] [unreadable]